A vaccine is needed to limit the worldwide spread of HIV-1 infection. Traditional approaches have not yielded a safe, effective vaccine. Exposure of rhesus monkeys to chimeric simian/human immunodeficiency viruses (SHIVs) is used to develop prophylactic strategies and to dissect the immune correlates that protect against virus exposure. Combinations of human anti-HIV-1 monoclonal antibodies (mAbs) neutralize SHIVs in a synergistic fashion, thereby requiring less antibody to achieve better neutralization. Recently, the P.I. passively administered the triple combination of human mAbs F105, 2G12, and 2F5 to rhesus monkeys prior to either mucosal or intravenous (i.v.) SHIV-vpu+ challenge. Each mAb-treated neonatal and adult monkey was completely protected from infection, providing evidence that antibodies reactive with these three epitopes can prevent systemic immunodeficiency virus infection following either mucosal or i.v. exposure. However, sera from HIV-infected individuals contain low or non-detectable levels of antibodies to the F105, 2G12 and 2F5-defined epitopes, demonstrating that these important, protective, native antigenic determinants are not immunodominant. Further, although mAb 2F5 interacts with a continuous, linear HIV-1 gp41 peptide sequence, protective human mAbs F105 and 2G12 recognize complex, discontinuous, conformationally dependent antigens which are unsuitable for use as vaccines. To overcome these obstacles, the P.I. proposes to: 1. Construct and immunoselect random peptide phage-displayed libraries for peptide mimics or "mimotopes" that bind to protective human anti-HIV-1 mAbs. 2. Immunize mice with phage particles displaying "mimotope" peptides and evaluate antisera for the ability to neutralize SHIV-vpu+ and HIV-1 strains in tissue culture. Flow cytometry will be used to detect virus-infected cells. Future studies will allow the P.I. to determine whether these mimetic epitopes protect SCID-hu reconstituted mice and non-human primates from immunodeficiency virus challenge.